Novel synthesis of heteroarylamine intermediate compounds

ABSTRACT

Disclosed are novel 2-(5-halopyridyl) and 2-(5-halopyrimidinyl) magnesium halides, processes of making and their use in the efficient synthesis in their respective 5-halo-2-substituted pyridines and pyrimidines.

APPLICATION DATA

[0001] This application is a divisional of U.S. application Ser. No.09/735,160 filed Dec. 12, 2000.

FIELD OF INVENTION

[0002] The present invention relates to synthesis of heteroarylamineintermediate compounds.

BACKGROUND OF THE INVENTION

[0003] Aryl- and heteroaryl-substituted ureas have been described asinhibitors of cytokine production. These inhibitors are described aseffective therapeutics in cytokine-mediated diseases, includinginflammatory and autoimmune diseases. Examples of such compounds arereported in WO 99/23091 and in WO 98/52558.

[0004] A key step in the synthesis of these compounds is the formationof the urea bond. Various methods have been reported to accomplish this.For example, as reported in the above references, an aromatic orheteroaromatic amine, II, may be reacted with an aromatic orheteroaromatic isocyanate III to generate the urea IV (Scheme I)

[0005] If not commercially available, one may prepare the isocyanate IIIby reaction of an aryl or heteroaryl amine Ar₂NH₂ with phosgene or aphosgene equivalent, such as bis(trichloromethyl) carbonate(triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937)or trichloromethyl chlorofonmate (diphosgene) (K. Kurita, T. Matsumuraand Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanateIII, followed by reaction with Ar₁NH₂ to provide the urea. Otherapproaches to forming the urea reported in the chemical literatureinclude reaction of a carbamate with an aryl or heteroaryl amine, (seefor example B. Thavonekham, Synthesis, 1997, 1189 and T. Patonay et al.,Synthetic Communications, 1996, 26, 4253) as shown in Scheme II belowfor a phenyl carbamate. U.S. patent application Ser. No. 09/611,109 alsodiscloses a process of making heteroaryl ureas by reacting particularcarbamate intermediates with the desired arylamine.

[0006] U.S. application Ser. No. 09/505,582 and PCT/US00/03865 describecytokine inhibiting ureas of formula (I).

[0007] An Ar₂NH₂ required to prepare preferred compounds describedtherein is illustrated as formula (A).

[0008] wherein W, Y, and Z are described below.

[0009] The synthesis of II, a preferred formula (A) intermediate wasdescribed in U.S. application Ser. No. 09/505,582 and PCT/US00/03865 andis illustrated in Scheme III.

[0010] The synthesis begins with a palladium catalyzed carbonylation of2,5-dibromopyridine (III) to provide ester IV in 55% yield. The reactionis run under pressure (80 psi CO) and must be monitored to minimizeformation of the diester, an unwanted by-product. Reduction of IV withdiisobutylaluminum hydride at −78° C. provides aldehyde V. This isfollowed by reductive amination to give VI.

[0011] Intermediate VI is then converted to II by reaction with t-BuLiat −78° C. followed by tributyltin chloride to give tributylstannaneVII, followed by palladium catalyzed Stille coupling with intermediateVIII to give II. Conversion of VI and analogous intermediates to otherintermediates of formula II via Suzuki coupling is also described inU.S. application Ser. No. 09/505,582 and PCT/US00/03865 (Scheme IV).According to this method, intermediate IX is treated with n-BuLifollowed by trimethylborate to give arylboronic acid X. Palladiumcatalyzed Suzuki coupling with VI provides XI, which is deprotected bytreatment with acid to give II.

[0012] This process is not well-suited for large-scale and commercialuse for several reasons. One reaction (Scheme III) is run under highpressure (80 psi) and another at extreme temperature (−78° C.). Theyield of IV is only moderate and by-product formation requires apurification step. These factors, plus the cost of starting materialsand reagents make this process too costly for commercial scale.

[0013] The preparation of 2-bromo-5-lithiopyridine via reaction of2,5-dibromopyridine with n-BuLi at −100° C. has been described (W. E.Parham and R. M. Piccirilli, J. Org. Chem., 1977, 42, 257). Theselective formation of 2-bromo-5-pyridinemagnesium chloride via reactionwith 2,5-dibromopyridine with i-PrMgCl at 0° C.—rt has also beenreported (F. Trecourt et al., Tetrahedron Lett., 1999, 40, 4339). Inthese cases, the metal-halogen exchange occurred exclusively at the 5position of the pyridine ring. However, the syntheses of5-bromo-2-pyridinemagnesium chloride and 5-chloro-2-pyridinemagnesiumchloride have not been reported previously.

[0014] The preparation of a lithium intermediate5-chloro-2-lithiopyridine from 2-bromo-5-chloropyridine, has beenreported (U. Lehmann et al., Chem., Euro. J., 1999, 5, 854). However,this synthesis requires reaction with n-BuLi at −78° C. The preparationof the 5-bromo-2-lithiopyridine from 2,5-dibromopyridine was reported byX. Wang et al. (Tetrahedron Letters, 2000, 4335). However, the methodrequires cryogenic and high dilution conditions. The selectivity wasalso dependent on reaction time. It is not suitable for large scalesynthesis.

[0015] The synthesis of the intermediate 5-bromo-2-iodopyridine byrefluxing 2,5-dibromopyridine in HI has been reported (U. Lehmann,ibid). A process using milder conditions for preparing 2-iodopyridinefrom 2-chloro or 2-bromopyridine has been described (R. C. Corcoran andS. H. Bang, Tetrahedon Lett., 1990, 31, 6757).

SUMMARY OF THE INVENTION

[0016] It is an object of the invention to provide novel2-(5-halopyridyl) and 2-(5-halopyrimidinyl) magnesium halides, novelmethods of producing them, and to provide a novel method of using saidhalides in the efficient synthesis of their respective5-halo-2-substituted pyridines and pyrimidines.

[0017] It also an object of the invention to provide a novel method ofproducing heteroaryl amines of the formula (A)

[0018] wherein Ar, W, Y and Z are described below, the heteroaryl aminesare useful in the production of heteroaryl ureas as mentioned above.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] This invention relates to a novel strategy for the synthesis ofheteroarylamine compounds of the formula (A) which constitute the keycomponent of pharmaceutically active compounds possessing a heteroarylurea group.

[0020] The invention therefore provides for processes of making acompound of the formula (A)

[0021] wherein:

[0022] W is CR₃ or N, wherein R₃ is chosen from hydrogen, C₁₋₅alkyl,C₁₋₅alkoxy, arylC₀₋₅alkyl and —COR₄ wherein R₄ is chosen from C₁₋₅alkyl,C₁₋₅alkoxy, arylC₀₋₅alkyl and amino which is optionally independentlydi-substituted by C₁₋₅alkyl, and arylC₀₋₅alkyl; W is preferably CH or N,

[0023] Ar is chosen from

[0024] phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl,dihydrobenzothienyl, indanyl, indenyl and indolyl each being optionallysubstituted by one or more R₁ or R₂;

[0025] Y is chosen from

[0026] a bond and a C₁₋₄ saturated or unsaturated branched or unbranchedcarbon chain optionally partially or fully halogenated, wherein one ormore methylene groups are optionally replaced by O, N, or S(O)_(m) andwherein Y is optionally independently substituted with one to two oxogroups, phenyl or one or more C₁₋₄ alkyl optionally substituted by oneor more halogen atoms;

[0027] wherein when Y is the carbon chain, the left side terminal atomof Y is a carbon (the atom which is covalently attached to theheterocycle possessing W):

[0028] Z is chosen from:

[0029] aryl, heteroaryl chosen from pyridinyl, piperazinyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, furanyl,thienyl and pyranyl and heterocycle chosen from tetrahydropyrimidonyl,cyclohexanonyl, cyclohexanolyl, 2-oxo- or2-thio-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl,pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylenesulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl,tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl,1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl,thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl anddioxolanyl, each of the aforementioned Z are optionally substituted withone to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl,C₁₋₆ alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, pyridinyl-C₁₋₃ alkyl,imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl,nitrile, phenyl wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy or mono- or di-(C₁₋₃ alkyl)amino, C₁₋₆alkyl-S(O)_(m), or phenyl-S(O)_(m) wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy, halogen or mono- ordi-(C₁₋₃ alkyl)amino;

[0030] or Z is optionally substituted with one to three amino oramino-C₁₋₃ alkyl wherein the N atom is optionally independently mono- ordi-substituted by amino C₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅alkoxyC₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)— orarylC₀₋₃alkyl-S(O)_(m)— each of the aforementioned alkyl and arylattached to the amino group is optionally substituted with one to twohalogen, C₁₋₆ alkyl or C₁₋₆ alkoxy;

[0031] or Z is optionally substituted with one to three aryl,heterocycle or heteroaryl as hereinabove described in this paragrapheach in turn is optionally substituted by halogen, C₁₋₆ alkyl or C₁₋₆alkoxy;

[0032] or Z is nitrile, amino wherein the N atom is optionallyindependently mono- or di-substituted by C₁₋₆alkyl orC₁₋₃alkoxyC₁₋₃alkyl, C₁₋₆alkyl branched or unbranched, C₁₋₆alkoxy,nitrileC₁₋₄alkyl, C₁₋₆ alkyl-S(O)_(m), aryl chosen from phenyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, furanyl, thienyl and pyranyl each aryl beingoptionally substituted with one to three halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m) or nitrile, andphenyl-S(O)_(m), wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy or mono- or di-(C₁₋₃ alkyl)amino;

[0033] R₁ and R₂ are independently chosen from:

[0034] a C₁₋₆ branched or unbranched alkyl optionally partially or fullyhalogenated, acetyl, aroyl, C₁₋₄ branched or unbranched alkoxy, eachbeing optionally partially or fully halogenated, halogen,methoxycarbonyl, C₁₋₃ alkyl-S(O)_(m) optionally partially or fullyhalogenated, or phenylsulfonyl;

[0035] m=0, 1 or 2;

[0036] All terms as used herein in this specification, unless otherwisestated, shall be understood in their ordinary meaning as known in theart. For example, “C₁₋₆alkoxy” is a C₁₋₆alkyl with a terminal oxygen,such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyland alkynyl groups shall be understood as being branched or unbranchedwhere structurally possible and unless otherwise specified. Other morespecific definitions are as follows:

[0037] Ac—acetyl;

[0038] DBA—dibenzylideneacetone;

[0039] DPPF—1,1′-bis(diphenylphosphino)ferrocene;

[0040] DPPE—1,2-bis(diphenylphosphino)ethane;

[0041] DPPB—1,4-bis(diphenylphosphino)butane;

[0042] DPPP—1,3-bis(diphenylphosphino)propane;

[0043] BINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;

[0044] DME—ethylene glycol dimethylether;

[0045] DMSO—dimethyl sulfoxide;

[0046] DMF—N,N-dimethylformamide;

[0047] EtO—ethoxide;

[0048]^(i)Pr—isopropyl;

[0049]^(t)Bu—tertbutyl;

[0050] THF—tetrahydrofuran;

[0051] RT or rt—room temperature;

[0052] The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

[0053] The term “aryl” as used herein shall be understood to meanaromatic carbocycle, preferably phenyl and naphthyl, or heteroaryl.

[0054] The term “heterocycle”, unless otherwise noted, refers to astable nonaromatic 4-8 membered (but preferably, 5 or 6 membered)monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radicalwhich may be either saturated or unsaturated. Each heterocycle consistsof carbon atoms and one or more, preferably from 1 to 4 heteroatomsselected from nitrogen, oxygen and sulfur. The heterocycle may beattached by any atom of the cycle, which results in the creation of astable structure. Unless otherwise stated, heterocycles include but arenot limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl,tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylenesulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl,homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl,decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl,dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or2-thia-5-aza-bicyclo[2.2.1]heptanyl.

[0055] The term “heteroaryl”, unless otherwise noted, shall beunderstood to mean an aromatic 5-8 membered monocyclic or 8-11 memberedbicyclic ring containing 1-4 heteroatoms such as N, O and S. Unlessotherwise stated, such heteroaryls include: pyridinyl, pyridonyl,quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl,tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl,benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl,benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl,indolinyl, indolonyl, indolinonyl, phthalimidyl.

[0056] Terms which are analogs of the above cyclic moieties such asaryloxy or heteroaryl amine shall be understood to mean an aryl,heteroaryl, heterocycle as defined above attached to it's respectivefunctional group.

[0057] As used herein, “nitrogen” and “sulfur” include any oxidized formof nitrogen and sulfur and the quaternized form of any basic nitrogen.

[0058] The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine except asotherwise noted. The compounds made by the novel processes of theinvention are only those which are contemplated to be ‘chemicallystable’ as will be appreciated by those skilled in the art. For example,a compound which would have a ‘dangling valency’, or a ‘carbanion’ arenot compounds made by processes contemplated by the invention.

[0059] In one embodiment of the invention there is provided a process ofmaking the compounds of formula (A) as described hereinabove,

[0060] said process comprising:

[0061] a) synthesis of a compound of formula (C) from a compound offormula (B) via substitution with an appropriate halide X_(c). WhenX_(c) is Br, methods known in the art may be utilized.

[0062] When X_(c) is I, the present invention provides a novel processfor the substitution of the leaving group (L) with iodide. This wasachieved by using the conditions of R_(x)COCl or (R_(x)CO)₂O/metaliodide/solvent/heating (25° C.-150° C.), wherein R_(x) is chosen from—C₁₋₇ alkyl, —CF₁₋₃ and —CCl₁₋₃; the metal chosen from Na and K, and thesolvent chosen from acetonitrile, acetone, DMSO, DMF and THF. Preferredconditions are AcCl and NaI in acetonitrile at 70-90° C. The leavinggroup L is any suitable leaving group as will be appreciated by thoseskilled in the art, preferably L is chosen from Cl, Br, —OCOR_(y) and—OS(O)_(m)R_(y), wherein R_(y) is aryl optionally substituted byC₁₋₄alkyl optionally halogenated, such as tolyl, or R_(y) is C₁₋₄alkyloptionally halogenated such as CF₃ and CCl₃, L is more preferably chosenfrom Br and Cl.

[0063] X_(a) is chosen from Br and Cl, preferably Br;

[0064] X_(c) is I or Br, preferably I;

[0065] X_(a) is attached via the 4 or 5 ring position, preferably the 5position.

[0066] b) In a one pot process, reacting a compound of the formula (C)with a Grignard reagent R—Mg—X_(b) followed by the addition of an E-Y-Zcompound wherein Y-Z is as defined above, said E-Y-Z component isfurther characterized as being an electrophilic derivative of Y-Z andbeing appropriate for Grignard reagant reactions as will be apparent tothe skilled artisan, said reaction taking place in a suitable aproticsolvent at −78° C. to RT, preferably 0° C. to RT for a reaction time of½ hour to 2 hours, preferably 1 hour, and isolating the compound of theformula (D);

[0067] wherein:

[0068] X_(b) is chosen from Br, Cl and I;

[0069] R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl;

[0070] As seen in Scheme V below, this one pot novel process stepprovides for the formation of the Grignard reagant Compound (F):

[0071] where a desirable selective formation was observed. For examplethe synthesis of 2-(5-halopyridyl)magnesium halides (e.g. 3 and 12) wasachieved for the first time.

[0072] The process of making compounds of the formula (F) comprises:

[0073] reacting a compound of the formula (C)

[0074] with a magnesium reagent of the formula R—MgX_(b); said reactiontaking place in a suitable aprotic solvent at −78° C. to RT, for areaction time of ½ hour to 2 hours, producing the Grignard compound ofthe formula (F); and wherein

[0075] X_(a), is halogen selected from Br and Cl, and X_(a) is attachedvia the 4 or 5 ring position;

[0076] X_(b) is halogen chosen from Br, Cl and I;

[0077] X_(c) is I or Br;

[0078] W is CR₃ or N, wherein R₃ is chosen from hydrogen, C₁₋₅alkyl,C₁₋₅alkoxy, arylC₀₋₅alkyl and —COR₄ wherein R₄ is chosen from C₁₋₅alkyl,C₁₋₅alkoxy, arylC₀₋₅alkyl and amino which is optionally independently ordi-substituted by C₁₋₅alkyl, and arylC₀₋₅alkyl; W is preferably CH or N;and

[0079] R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl.

[0080] In a preferred embodiment there is provided a process for makinga compound of the formula (F) as described above and wherein

[0081] W is CH;

[0082] X_(a) is Br and attached at the 5 ring position;

[0083] X_(c) is I;

[0084] the temperature is 0° C. to RT; and

[0085] the reaction time is 1 hour.

[0086] Non-limiting examples of this reaction proceeded with completeselectivity at the 2 position in excellent yield:

[0087] In subsequent steps, the novel process of the invention furthercomprises:

[0088] c) reacting the compound of the formula (D) from step b) with anaryl boronic acid of the formula (E), in the presence of a catalystchosen from nickel and palladium. Regarding the palladium (Pd) catalyst,non-limiting examples are Pd catalysts chosen from Pd(PPh₃)₂Cl₂,Pd(PPh₃)₄, PdCl₂(DPPE), PdCl₂(DPPB), PdCl₂(DPPP), PdCl₂(DPPF) and Pd/C;or the combination of a palladium source and an appropriate ligand, withthe Pd source, for example, being chosen from PdCl₂, Pd(OAc)₂,Pd₂(DBA)₃, Pd(DBA)₂, and with the ligand being chosen from PPh₃, DPPF,DPPP, DPPE, DPPB, P(o-tolyl)₃, P(2,4,6-trimethoxyphenyl)₃, AsPh₃,P(^(t)Bu)₃, BINAP, and those bound to solid supports that are mimics ofthe aforementioned ligands, preferably PdCl₂ and PPh₃. Regarding thenickel (Ni) catalyst, examples of nickel (Ni) catalyst are those chosenfrom Ni(PPh₃)₂Cl₂, Ni(PPh₃)₄, NiCl₂(DPPE), NiCl₂(DPPB), NiCl₂(DPPP),NiCl₂(DPPF) and Ni/C; or the combination of a Ni source and anappropriate ligand, with the Ni source being NiCl₂, and with the ligandbeing chosen from PPh₃, DPPF, DPPP, DPPE, DPPB, P(o-tolyl)₃,P(2,4,6-trimethoxyphenyl)₃, AsPh₃, P(^(t)Bu)₃, BINAP, and those bound tosolid supports that are mimics of the aforementioned ligands. Thisreaction takes place in a suitable solvent such as ethylene glycoldimethyl ether (DME), THF, toluene, methylene chloride or water,preferably DME, at 0° C. to 150° C., preferably 25° C. to 100° C., for aperiod of 1 to 24 hours preferably about 15 hours,

[0089] wherein P in the formula (E) is an amino protecting group such asBoc, and subsequently removing said protecting group under suitableconditions to produce a compound of the formula (A).

[0090] In a preferred embodiment of the invention there is provided anovel process of making compounds of the formula (A) as described aboveand wherein:

[0091] W is CH;

[0092] Ar is chosen from naphthyl, quinolinyl, isoquinolinyl,tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,indanyl, indenyl and indolyl each being optionally substituted by one ormore R₁ or R₂ groups;

[0093] Y is chosen from:

[0094] a bond and

[0095] a C₁₋₄ saturated or unsaturated carbon chain wherein one of thecarbon atoms is optionally replaced by O, N, or S(O)_(m) and wherein Yis optionally independently substituted with one to two oxo groups,phenyl or one or more C₁₋₄ alkyl optionally substituted by one or morehalogen atoms; wherein when Y is the carbon chain, the left sideterminal atom of Y is a carbon (the atom which is covalently attached tothe heterocycle possessing W):

[0096] Z is chosen from:

[0097] phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolylsulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted withone to three nitrile, C₁₋₃ alkyl, C₁₋₃ alkoxy, amino or mono- ordi-(C₁₋₃ alkyl)amino;

[0098] tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl,1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl,tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylenesulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl,tetramethylene sulfoxidyl or tetramethylene sulfonyl which areoptionally substituted with one to three nitrile, C₁₋₃ alkyl, C₁₋₃alkoxy, amino or mono- or di-(C₁₋₃ alkyl)amino; nitrile, C₁₋₆alkyl-S(O)_(m), halogen, C₁₋₄ alkoxy, amino, mono- or di-(C₁₋₆alkyl)amino and di-(C₁₋₃alkyl)aminocarbonyl;

[0099] In a more preferred embodiment of the invention there is provideda novel process of making compounds of the formula (A) as describedimmediately above and wherein:

[0100] Ar is naphthyl;

[0101] Y is chosen from:

[0102] a bond and

[0103] a C₁₋₄ saturated carbon chain wherein the left side terminal atomof Y is a carbon (the atom which is covalently attached to theheterocycle possessing W) and one of the other carbon atoms isoptionally replaced by O, N or S and wherein Y is optionallyindependently substituted with an oxo group;

[0104] Z is chosen from:

[0105] phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl andpyrrolidinyl which are optionally substituted with one to two C₁₋₂ alkylor C₁₋₂ alkoxy;

[0106] tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinylsulfoxidyl, piperidinyl, piperidinonyl, piperazinyl andtetrahydropyrimidonyl which are optionally substituted with one to twoC₁₋₂ alkyl or C₁₋₂ alkoxy; and

[0107] C₁₋₃ alkoxy;

[0108] In yet a more preferred embodiment of the invention there isprovided a novel process of making compounds of the formula (A) asdescribed immediately above and wherein:

[0109] Ar is 1-naphthyl wherein the NH₂ is at the 4 position;

[0110] Y is chosen from:

[0111] a bond, —CH₂—, —CH₂CH₂— and —C(O)—,;

[0112] In an ultimately preferred embodiment of the invention there isprovided a novel process of making compounds of the formula (A) asdescribed immediately above and wherein:

[0113] Y is

[0114] —CH₂—;

[0115] Z is morpholinyl;

[0116] Formation of the reaction intermediate (E) can be accomplished byfirst protecting an aryl-amine followed by boronic acid formationthrough a sequence of metal-bromine exchange, quenching withtrialkylborate and hydrolysis, as can be seen in Scheme V in theconversion of 7 to 9. Compounds of the formula (E) possessing otherdesired Ar can be accomplished without undue experimentation byvariations apparent to those of ordinary skill in the art in view of theteachings in this specification and the state of the art.

[0117] A desirable novel feature of the process of the invention is theselective formation of a 2-(5-halopyridyl) or 2-(5-halopyrimidinyl)magnesium halides, preferably 2-(5-halopyridyl) magnesium halides (e.g.3 and 12, vide infra), and their subsequent reactions with the in situgenerated E-Y-Z electrophiles. Below in Scheme 1, the addition of2-(5-halopyridyl) magnesium halide 3 to the immonium salt 6 was carriedout without the isolation of the immonium salt.

[0118] A non-limiting example for a compound of the formula (A) is theamine 1 shown in Scheme V.

[0119] Reaction intermediate (2) with a generic formula (B) above can beobtained as exemplified in Scheme VI below. Addition of a coppercatalyst may be required for transformations involving certain types ofelectrophiles, for example the alkylation reaction of the Grignardintermediate with various alkyl halides and epoxides.

[0120] Examples of appropriate electrophiles are shown in the tablebelow. Methods of making Y-Z electrophilic derivatives are within theskill in the art. Y component in Y-Z is a derivative of the Y of theformula (A) of the final product upon the addition of the electrophileto the Grignard intermediate. Products may be further derivatized toachieve the desired Y-Z. Such further transformations are within theskills in the art. A non-limiting example is shown below for a preferredembodiment of Z in the formula (A), i.e., the morpholino immonium salt6. Reference in this regard may be made to Heaney, H.; Papageorgiou, G.;Wilkins, R. F. Tetrahedron 1997, 53, 2941; Sliwa, H.; Blondeau, D.Heterocycles 1981, 16, 2159;.

[0121] In this example, E-Y-Z is compound 6, wherein morpholinylrepresents Z and Y is —CH₂— in the final product.

[0122] As described above, any electrophile represented by Y, possessinga Z component and compatible with Grignard type reactions arecontemplated to be within the scope of the invention. Additionalnon-limiting examples of E-Y-Z are: Electrophiles Product (X = Br orCl) 1. Z-CHO

wherein E-Y is an aldehyde such as Z-CHO, thus Y in Formula (A) would be—CH(OH)—. 2.

wherein NRR represent any of the above-listed Z amine moieties orheterocycles possessing a nitrogen heteroatom and Y can be alkylene suchas —CH₂—, X is a countervalent anion. 3. X—(CH₂)₁₋₄—O-Z

wherein E-Y is a branched or unbranched alkoxy possessing a halogen atomX and further linked to Z, such as ClCH₂—O-Z. 4.

wherein E-Y is a C₁₋₄acyl halide such as formylchloride, NRR′ representsany of the above-listed Z amine moieties, or heterocycles possessing anitrogen heteroatom. LG is an appropriate leaving group such ashalogens. (see: Katritzky et al., J. Chem. Res. 1999, 3, 230.) 5.

wherein E-Y is a haloester moiety such as chloroformate. X is anappropriate leaving group such as halogens or alkoxy groups. (see:Satyanarayana et al., Synth. Commun. 1990, 20 (21), 3273.) 6. Z-Y-Xwherein an appropriate Z-Y is substituted by halogen X, prefereablyiodine, such as CH₃I. 7.

Addition of an appropriate Z attached to a reactive epoxide provides thehydroxy intermediate which is further derivatized to the desired Ycomponent. 8.

Acylation wherein Y is an acyl attached to Z may be accomplished via theappropriate acylation reagent such as the ester shown above wherein —ORis a known leaving group. In another embodiment of the invention thereis provided a process of making the compounds of formula(A): (A)

wherein Ar and W are as described above;

[0123] and wherein for the formula (A):

[0124] Y is —CH₂—; and

[0125] Z is chosen from:

[0126] heterocycle chosen from morpholinyl, thiomorpholinyl, piperidinyland pyrrolidinyl each of the aforementioned Z are optionally substitutedwith one to three halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₆ alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, pyridinyl-C₁₋₃ alkyl,imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl,nitrile, phenyl wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy, di-(C₁₋₃ alkyl)amino, C₁₋₆alkyl-S(O)_(m), or phenyl-S(O)_(m) wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy or di-(C₁₋₃alkyl)amino;

[0127] or Z is optionally substituted with one to three one to threeamino or amino-C₁₋₃ alkyl wherein the N atom is optionally independentlydi-substituted by aminoC₁₋₆alkyl, C₁₋₃alkyl, arylC₀₋₃alkyl, C₁₋₅ alkoxyC₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl, C₁₋₃alkyl-S(O)_(m)—orarylC₀₋₃alkyl-S(O)_(m)— each of the aforementioned alkyl and arylattached to the amino group is optionally substituted with one to twohalogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; or Z is optionally substituted withone to three aryl or heterocycle as hereinabove described in thisparagraph each in turn is optionally substituted by halogen, C₁₋₆ alkylor C₁₋₆ alkoxy;

[0128] or Z is amino wherein the N atom is optionally independentlymono- or di-substituted by C₁₋₆alkyl or C₁₋₃alkoxy C₁₋₃alkyl, C₁₋₆alkylbranched or unbranched, C₁₋₆alkoxy, nitrileC₁₋₄alkyl, C₁₋₆alkyl-S(O)_(m), aryl chosen from phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,furanyl, thienyl and pyranyl each aryl being optionally substituted withone to three halogen, C₁₋₆ alkyl, Cl-6 alkoxy, di-(C₁₋₃ alkyl)amino,C₁₋₆ alkyl-S(O)_(m) or nitrile, and phenyl-S(O)_(m), wherein the phenylring is optionally substituted with one to two halogen, C₁₋₆ alkoxy ormono- or di-(C₁₋₃ alkyl)amino;

[0129] said reaction comprising:

[0130] reacting a compound of the formula (C)

[0131] with a magnesium reagent of the formula R—MgX_(b); said reactiontaking place in a suitable aprotic solvent at −78° C. to RT, for areaction time of ½ hour to 2 hours producing the Grignard compound (F):

[0132] wherein

[0133] X_(a), is halogen selected from Br and Cl, and X_(a) is attachedto the ring via the 4 or 5 position;

[0134] X_(b) is halogen chosen from Br, Cl and I;

[0135] X_(c) is I or Br;

[0136] W is CH, CCH₃ or N; and

[0137] R is aryl, C₁₋₆alkyl or C₅₋₇cycloalkyl;

[0138] subsequently reacting the Grignard compound from the prior stepwith a N,N-dialkylformamide such as DMF to form an aldehyde:

[0139] and isolating the aldehyde;

[0140] reacting the aldehyde with an appropriate Z group undernucleophilic addition conditions to provide the compound (D)

[0141] This transformation is within the skill in the art and involvesreacting of the aldehyde and the appropriate Z component under acidicconditions such as HCl, AcOH, H₂SO₄ etc, preferably AcOH, in a suitablesolvent such as THF, methylene chloride, 1,2-dichloroethane, preferably1,2-dichloroethane for 0.5-5 h (preferably 2 h) at about RT followed byin situ reduction for 0.5-5 h (preferably 2 h) to provide the product(D).

[0142] Subsequent addition of the NH₂—Ar compound can be done asdescribed hereinabove, to provide the final product compound of theformula (A) as described above in this embodiment of the invention. Anon-limiting example of this embodiment of the invention is shown inScheme VII.

[0143] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

SYNTHETIC EXAMPLES Example 1

[0144] Synthesis of 5-bromo-2-iodopyridine from 2,5-dibromopyridine

[0145] 2,5-Dibromopyridine (100 g) was suspended in acetonitrile (500mL) at rt. NaI (94 g) and AcCl (45 mL) were added and the reaction wasthen gently refluxed for 3 h. An aliquot was analyzed by ¹H NMR and MSand the reaction was about 80% complete. The reaction was cooled to rtand quenched with a few mL of water and then K₂CO₃ aqueous solution topH 8. EtOAc (1.5 L) was added to extract the organic materials. Theorganic layer was washed with saturated NaHSO₃ solution, the brine, andthen dried over MgSO₄. Concentration gave crude material that wassubjected to the same conditions for about 3 h at which time ¹H NMRshowed that the reaction was greater than 97% complete. The same workupprovided the crude material. The crude crystals were washed twice withCH₃CN and dried in the oven. The yield was 95 g.

[0146]¹H NMR (CDCl₃, 400 MHz) δ 8.44 (s, 1H), 7.60 (d, J=8.26 Hz, 1H),7.44 (d, J=8.25 Hz, 1H).

Example 2

[0147] Synthesis of 5-bromo-2-formylpyridine from 5-bromo-2-iodopyridinevia the Grignard Intermediate

[0148] In a 22 L 3-neck round bottomed flask equipped with a mechanicalstirrer, 1 kg (3.52 mol) of 2-iodo-5-bromopyridine was dissolved in 5 Lof THF. The solution was cooled to about −15 to −10° C. 1.9 L (2 M, 380mol, 1.08 eq) of ^(i)PrMgCl was added at a rate to keep the internaltemperature below 0° C. The reaction mixture became a brown suspension.After the reaction mixture was stirred between −15 to 0° C. for 1 h, 400mL (5.16 mol, 1.5 eq) of DMF was added at a rate to keep the internaltemperature below 0° C. After stirring at this temperature for 30 min,the cooling bath was removed and the reaction was allowed to warm toroom temperature over 1 h. The reaction mixture was then cooled to 0° C.and 4.0 L (7.74 mol, 2.2 eq) of 2 N HCl was added at a rate to keep theinternal temperature below 25° C. The mixture was stirred for 30 min,then pH was raised from 1 to a pH 6-7 by adding about 150 mL of 2 NNaOH. The layers were separated and the THF layer was concentrated togive dark brown wet solids. The aqueous layer was extracted with 3 L ofCH₂Cl₂. The CH₂Cl₂ layer was used to dissolve the residue obtained fromthe THF layer, the resulting solution was washed with water (2×2 L),dried by stirring with MgSO₄ (400 g) for 30 min, and filtered.Concentration of the filtrate to dryness gave 583 g of the desiredaldehyde as brownish-yellow solids (89% yield after air drying).

[0149]¹H NMR (CDCl₃, 400 MHz) δ 10.04 (d, J=0.68 Hz, 1H), 8.86 (t,J=0.52 Hz, 1H), 8.02 (dt, J=8.20, 0.68 Hz, 1H), 7.85 (d, J=8.48 Hz, 1H).

Example 3

[0150] Synthesis of 5-bromo-2-(4-morpholinylmethyl)pyridine from5-bromo-2-iodopyridine via the Grignard Intermediate

[0151] To a solution of bis(l-morpholinyl)methane (130 mg) in THF (3 mL)at rt was added acetyl chloride (45 mL). The reaction was stirred for 1h and cooled to 0° C.

[0152] In another flask, 5-bromo-2-iodopyridine (130 mg) was dissolvedin THF (3 mL) at −40° C. The solution was treated with ^(i)PrMgCl (2 Min THF, 0.39 mL) at the same temperature for 15 min. Then the Grignardsolution was cannulated into the immonium salt suspension generatedabove at 0° C. After the addition, the reaction mixture was stirred atrt for 1h and quenched with saturated NH₄Cl solution. Extraction withCH₂Cl₂, drying over MgSO₄, filtration and concentration gave a crudeoil. This was further purified by column chromatography to afford theproduct in about 50% yield.

[0153]¹H NMR (CDCl₃, 400 MHz) δ 8.60 (s, 1H), 7.76 (d, J=8.24 Hz, 1H),7.32 (d, J=8.64 Hz, 1H), 3.72 (m, 4H), 3.59 (s, 2H), 2.48 (m, 4H).

Example 4

[0154] Synthesis of 5-bromo-2-(4-morpholinyl)methylpyridine from5-bromo-2-formylpyridine

[0155] To a solution of 500 g (2.688 moles) aldehyde in a 5 L of 1,2-dichloroethane at room temperature was added morpholine (1.15 eq, 3.09moles, 269 ml) in one portion. The reaction temperature went up to 29°C. After stirring the reaction mixture for 15 min, acetic acid (2.1 eq,5.6 moles, 323 mL) was added in one portion. The temperature rose to 31°C. It was stirred for 1.5 h at room temperature. Sodiumtriacetoxyborohydride (1.06 eq, 2.85 moles, 604 g) was added in 100 gportions every 10 min. The temperature was maintained between 35° C. and46° C. by gentle cooling. It was stirred for an additional 2 h.

[0156] The reaction mixture was quenched with 4 N HCl keeping thetemperature below 15° C. At the end of addition, the pH of aqueous phasewas between 0 and 1 (˜2200 mL). The organic phase was separated anddiscarded. The aqueous phase was basified with 9 N NaOH (˜740 g NaOH) topH ˜9.5 keeping the internal temperature below 15° C. The product wasextracted with methylene chloride. Evaporation of the solvent gave pureamine (660 g, 2.57 moles).

Example 5

[0157] Synthesis of 5-Bromo-3-methyl-2-pyridinecarboxaldehyde

[0158] An example of the synthesis of a compound of formula (F) in whichW is CR₃ (R₃=methyl), and subsequent reaction with an electrophile isprovided below and illustrated in Scheme VIII.

[0159] 2,5-Dibromo-3-picoline is commercially available or may beprepared from 2-amino-5-bromo-3-methylpyridine by standard diazotizationfollowed by bromination in Br₂/HBr. Acetyl chloride (0.68 mol, 52.7 mL)was added to a stirring solution of 2,5-dibromo-3-picoline (0.45 mol,113 g) in acetonitrile (600 mL) followed by sodium iodide (1.66 mol, 250g) and the reaction mixture was gently refluxed for 18 h. The cooledreaction mixture was filtered and the solid was washed with acetonitrileuntil colorless. It was suspended in methylene chloride and treated withaq. Na₂CO₃ until the pH was 10-11. The organic layer was separated,dried over anhydrous sodium sulfate and concentrated to give a brownoil. It was subjected to iodination a second time as above (reflux time6 h). A dark brown oil was obtained using the same work-up as above. Asolution of this oil in hexane was treated with charcoal, filtered andconcentrated to give a light brown oil. It slowly solidified on standingto give 5-bromo-2-iodo-3-methylpyridine as a light brown solid (95.0 g,0.32 mol). Yield: 70%.

[0160] 2-Iodo-5-bromo-3-methylpyridine (250 mg) was dissolved in THF(4.0 mL). The solution was cooled to 0° C. ^(i)PrMgCl (2 M in THF, 0.5mL) was added at a rate to keep the internal temperature below 5° C.After the reaction mixture was stirred at 0° C. for 1 h, DMF (0.13 mL)was added at 0° C. After stirring at this temperature for 30 min, thecooling bath was removed and the reaction was allowed to warm to roomtemperature over 1 h. The reaction mixture was hydrolyzed by a saturatedaqueous NH₄Cl solution. Then the aqueous layer was extracted withCH₂Cl₂. The CH₂Cl₂ layer was dried over MgSO₄ and concentrated to givethe desired aldehyde as a brownish-yellow solid (80% yield).

What is claimed is:
 1. A process of making the compounds of formula (A):

wherein Ar Ar is chosen from: phenyl, naphthyl, quinolinyl,isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl,dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl,indanyl, indenyl and indolyl each being optionally substituted by one ormore R₁ or R₂; W is CR₃ or N, wherein R₃ is chosen from hydrogen,C₁₋₅alkyl, C₁₋₅alkoxy, arylC₀₋₅alkyl and —COR₄ wherein R₄ is chosen fromC₁₋₅alkyl, C₁₋₅alkoxy, arylC₀₋₅alkyl and amino which is optionallyindependently mono or di-substituted by C₁₋₅alkyl, and arylC₀₋₅alkyl; R₁and R₂ are independently chosen from: a C₁₋₆ branched or unbranchedalkyl optionally partially or fully halogenated, acetyl, aroyl, C₁₋₄branched or unbranched alkoxy, each being optionally partially or fullyhalogenated, halogen, methoxycarbonyl, C₁₋₃ alkyl-S(O)_(m) optionallypartially or fully halogenated or phenylsulfonyl; m=0, 1 or 2; andwherein for the formula (A): Y is —CH₂—; and Z is: heterocycle chosenfrom morpholinyl, thiomorpholinyl, piperidinyl and pyrrolidinyl each ofthe aforementioned Z are optionally substituted with one to threehalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₃ alkoxy-C₁₋₃ alkyl, C₁₆alkoxycarbonyl, aroyl, C₁₋₃acyl, oxo, pyridinyl-C₁₋₃ alkyl,imidazolyl-C₁₋₃ alkyl, tetrahydrofuranyl-C₁₋₃ alkyl, nitrile-C₁₋₃ alkyl,nitrile, phenyl wherein the phenyl ring is optionally substituted withone to two halogen, C₁₋₆ alkoxy, di-(C₁₋₃ alkyl)amino, C₁₋₆alkyl-S(O)_(m) or phenyl-S(O)_(m) wherein the phenyl ring is optionallysubstituted with one to two halogen, C₁₋₆ alkoxy or di-(C₁₋₃alkyl)amino; or Z is optionally substituted with one to three one tothree amino or amino-C₁₋₃ alkyl wherein the N atom is optionallyindependently mono- or di-substituted by aminoC₁₋₆alkyl, C₁₋₃alkyl,arylC₀₋₃alkyl, C₁₋₅alkoxy C₁₋₃ alkyl, C₁₋₅ alkoxy, aroyl, C₁₋₃acyl,C₁₋₃alkyl-S(O)_(m)- or arylC₀₋₃alkyl-S(O)_(m)- each of theaforementioned alkyl and aryl attached to the amino group is optionallysubstituted with one to two halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; or Z isoptionally substituted with one to three aryl or heterocycle ashereinabove described in this paragraph each in turn is optionallysubstituted by halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; or Z is amino whereinthe N atom is optionally independently mono- or di-substituted byC₁₋₆alkyl or C₁₋₃alkoxy C₁₋₃alkyl, C₁₋₆alkyl branched or unbranched,C₁₋₆alkoxy, nitrileC₁₋₄alkyl, C₁₋₆ alkyl-S(O)_(m), aryl chosen fromphenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl each arylbeing optionally substituted with one to three halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, di-(C₁₋₃ alkyl)amino, C₁₋₆ alkyl-S(O)_(m) or nitrile; saidreaction comprising: i) reacting a compound of the formula (C)

with a magnesium reagent of the formula R—MgX_(b); said reaction takingplace in a suitable aprotic solvent at −78° C. to RT, for a reactiontime of ½ hour to 2 hours producing the Grignard compound (F):

wherein X_(a) is chosen from Br and Cl, and X_(a) is attached to thering via the 4 or 5 position; X_(b) is chosen from Br, Cl and I; X_(c)is chosen from I and Br; wherein X_(a) and X_(c) are not the same; and Ris chosen from aryl, C₁₋₆alkyl and C₅₋₇cycloalkyl; ii) subsequentlyreacting the Grignard compound(F) from the prior step with aN,N-dialkylformamide to form an aldehyde, and isolating the aldehyde;iii) reacting the aldehyde in step ii) with an appropriate Z group underacid conditions in a suitable solvent to provide the compound (D):

reacting the compound of the formula (D) with an aryl boronic acid ofthe formula (E) and a palladium catalyst, in the presence of anappropriate ligand, in a suitable solvent at 0° C. to 150° C., for about1 to 24 hours:

wherein P in the formula (E) is an amino protecting group, andsubsequently removing said protecting group under suitable conditions toproduce a compound of the formula (A).
 2. The process according to claim1 wherein W is CH or N.
 3. The process according to claim 3 wherein instep i): X_(a) is Br and attached at the 5 ring position; X_(c) is I; Wis CH; R is C₁₋₆alkyl; in step ii): the N,N-dialkylformamide is DMF; thealdehyde is:

in step iii): the acidic conditions use an acid chosen from HCl, AcOH,H₂SO₄; the solvent is chosen from THF, methylene chloride and1,2-dichloroethane; the time is about 2 h at about RT followed by insitu reduction for about 2 h.
 4. The process according to claim 3wherein: in step i) R is isopropyl; and in step iii) the acid is AcOH;and the solvent is 1,2-dichloroethane.